Despite extensive efforts, no or few promising HIV vaccine candidate has emerged. Since the natural immune response to HIV is ineffective, it may be necessary to generate immune responses that are superior to the natural anti-HIV immune responses. Thus, there is an urgent need to explore alternative immunization approaches. Antigen-presenting cells (APCs) play a critical role in the initiation and maintenance of immune response against HIV infection, and are regulated by stimulatory as well as inhibitory signaling. The suppressor of cytokine signaling 1 (SOCS1) plays a critical inhibitory role in immune responses by blocking the JAK-STAT signaling pathway in APCs. Our recent studies demonstrate that the stimulatory capacity of DCs and the magnitude of adaptive immunity are critically controlled by SOCS1 in DCs, and SOCS1-silenced DCs induce an enhanced CTL and antibody response against HIV antigens. The goal of this study is to develop an effective vaccination strategy to prevent or control HIV infection by the inhibition of cytokine signaling inhibitors in APCs. The central hypothesis of this study is that in vivo vaccination with lentiviral vectors coexpressing siSOCSl and a modified HIV immunogen silences the JAK/STAT signaling inhibitor SOCS1 in transduced APCs, thus enhancing their immunostimulatory potency, prolonging their survival, and endowing them with the ability to persistently stimulate HIV-specific cellular and humoral responses. The specific aims of this study are: 1) To test the hypothesis that in vivo immunization with lentiviral vectors coexpressing SiSOCSl, which inhibits the key inhibitor of JAK/STAT signaling, and a modified HIV immunogen enhances the ability of HIV vaccine to induce both HIV-specific CD8+ and CD4+ T cell and antibody responses. 2) To test the hypothesis that coexpression of a proinflammatory cytokine and the inhibitor of its signaling inhibitor (siSOCSl) more efficiently induces memory HIV-specific CD8+ and CD4+ T cell and antibody responses. 3) To test the hypothesis that SOCS1-silenced antigen-presenting cells transduced by in vivo lentiviral immunization can persistently activate HIV-specific cellular and humoral responses. This vaccination strategy proposed in this study, to our knowledge, represents the first example of enhancing anti-HIV immunity by inhibiting a host's signaling inhibitor. This SOCS1 silencing approach could be generally applicable to enhancing the potency of various forms of HIV vaccines. Importantly, this study aims to develop a HIV vaccine candidate, which could be further evaluated in non-human primates and ultimately in humans.